Blocking phosphatidylglycerol degradation in yeast defective in cardiolipin remodeling results in a new model of the Barth syndrome cellular phenotype

Káňovičová, Paulína; C̆ermáková, Petra; Kubalová, Dominika; Babelova, Lenka; Veselá, Petra; Valachovič, Martin; Zahumensky, Jakub; Horváth, Anton; Malínský, J; Balážová, Mária

doi:10.1016/j.jbc.2021.101462

Cited by 3 publications

(13 citation statements)

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“…In addition, wild type-like PE levels could be restored by PGC1 deletion in isc1Δ strain. In accordance with the previously published data, we also found lower PC content in the two strains lacking the PGC1 allele (Káňovičová et al, 2022), and a small but statistically significant decrease of PC levels was detected in sch9Δ strain, too.…”

Section: Resultssupporting

confidence: 93%

“…Analogous to pgc1Δisc1Δ, the pgc1∆taz1∆ strain accumulated PG. Consistent with our recent data, it could be the lower DAG production associated with the PGC1 deletion that led to the observed restoration of Pgs1 activity in pgc1∆taz1∆ cells (Káňovičová et al, 2022).…”

Section: Diacylglycerol Inhibits Pg Synthesissupporting

confidence: 92%

“…Intact mitochondria were isolated from the cells grown to diauxic shift as described previously (Pokorná et al , 2016). The final mitochondrial pellet was suspended in the respiration buffer (0.6 M mannitol, 20 mM HEPES/KOH pH 7.1, 2 mM MgCl 2 , 1 mM EGTA, 0.1 % fatty acid-free bovine serum albumin, 10 mM KH 2 PO 4 ) and used for measurement of O 2 consumption (OXPHOS capacity) as described in (Káňovičová et al , 2022), the activity of cytochrome c reductase and the activity of cytochrome c oxidase was measured as described in (Pokorná et al , 2016).…”

Section: Methodsmentioning

confidence: 99%

“…Activity of Pgs1 was determined by quantification of the incorporation of radiolabeled substrate [ 14 C]glycerol-3-phosphate into chloroform-soluble products as described previously (Káňovičová et al , 2022).…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we asked whether elevated PG levels themselves could at least partially rescue the phenotype of isc1∆ cells. Deletion of PGC1 gene has been shown before to induce PG accumulation in various backgrounds (Pokorná et al, 2016;Kubalová et al, 2019;Káňovičová et al, 2022). Therefore, we constructed pgc1∆isc1∆ double deletion mutant.…”

Section: Introductionmentioning

confidence: 99%

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Two different phospholipases C, Isc1 and Pgc1, cooperate to regulate mitochondrial function

Balážová

Babelova

Durisova

et al. 2022

Preprint

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Absence of inositolphosphosphingolipid phospholipase C, Isc1, a yeast homologue of mammalian neutral sphingomyelinase type 2, leads to severe mitochondrial dysfunction. We show that the defect can be largely rescued by deletion of another type-C phospholipase, the phosphatidylglycerol (PG)-specific Pgc1. The reduced phosphatidylethanolamine (PE) levels, as well as reduced cytochrome c oxidase activity, observed in isc1Δ cells were restored to wild-type levels in the pgc1Δisc1Δ mutant. We found that Pgc1 substrate, PG, inhibits in vitro activity of Isc1 and phosphatidylserine decarboxylase Psd1, an enzyme crucial for PE biosynthesis. We also identified a mechanism by which the balance between the current demand for PG and its consumption is controlled. We document that the product of PG hydrolysis, diacylglycerol, competes with the substrate of PG-phosphate synthase, Pgs1, and thereby inhibits the biosynthesis of excess PG. This feedback loop does not work in the absence of Pgc1, which catalyzes PG degradation. Finally, Pgc1 activity is partially inhibited by products of Isc1-mediated hydrolysis. The described functional interconnection of the two phospholipases contributes significantly to lipid homeostasis throughout the cellular architecture.

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Section: Resultssupporting

confidence: 93%

Section: Diacylglycerol Inhibits Pg Synthesissupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two different phospholipases C, Isc1 and Pgc1, cooperate to regulate mitochondrial function

Balážová

Babelova

Durisova

et al. 2022

Preprint

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A patatin-like phospholipase is important for mitochondrial function in malaria parasites

Pietsch,

Ramaprasad,

Bielfeld

et al. 2023

mBio

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Plasmodium parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are validated antimalarials. Here, we localize Plasmodium falciparum patatin-like phospholipase 2 ( Pf PNPLA2, PF3D7_1358000) to the mitochondrion and reveal that disruption of the Pf PNPLA2 gene impairs asexual replication. Pf PNPLA2-null parasites are hypersensitive to proguanil and inhibitors of the mitochondrial ETC, including atovaquone. In addition, Pf PNPLA2-deficient parasites show reduced mitochondrial respiration and reduced mitochondrial membrane potential, indicating that disruption of Pf PNPLA2 leads to a defect in the parasite ETC. Lipidomic analysis of the mitochondrial phospholipid cardiolipin (CL) reveals that loss of Pf PNPLA2 is associated with a moderate shift toward shorter-chained and more saturated CL species, implying a contribution of Pf PNPLA2 to CL remodeling. Pf PNPLA2-deficient parasites display profound defects in gametocytogenesis, underlining the importance of a functional mitochondrial ETC during both the asexual and sexual development of the parasite. IMPORTANCE For their proliferation within red blood cells, malaria parasites depend on a functional electron transport chain (ETC) within their mitochondrion, which is the target of several antimalarial drugs. Here, we have used gene disruption to identify a patatin-like phospholipase, Pf PNPLA2, as important for parasite replication and mitochondrial function in Plasmodium falciparum . Parasites lacking Pf PNPLA2 show defects in their ETC and become hypersensitive to mitochondrion-targeting drugs. Furthermore, Pf PNPLA2-deficient parasites show differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions. Finally, we demonstrate that parasites devoid of Pf PNPLA2 have a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector.

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Two Different Phospholipases C, Isc1 and Pgc1, Cooperate To Regulate Mitochondrial Function

et al. 2022

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Blocking phosphatidylglycerol degradation in yeast defective in cardiolipin remodeling results in a new model of the Barth syndrome cellular phenotype

Cited by 3 publications

References 61 publications

Two different phospholipases C, Isc1 and Pgc1, cooperate to regulate mitochondrial function

Two different phospholipases C, Isc1 and Pgc1, cooperate to regulate mitochondrial function

A patatin-like phospholipase is important for mitochondrial function in malaria parasites

Two Different Phospholipases C, Isc1 and Pgc1, Cooperate To Regulate Mitochondrial Function

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